The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experience by asthmatics [See, e.g. B. Samuelson et al., Science, 237:1117-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J., 259: 325-324 (1989) from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX-1 and COX-2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A2 (hereinafter PLA2). The reaction catalyzed by PLA2 is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLA2 is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58 (1998)].
Most anti-inflammatory therapies have focused on preventing production of either protaglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-1/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathwasy of conversion of arachidonic acid to leukotrienes, witout affecting the production of prostaglandins. None of these widelt-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol., 3:2429-2436 (1987)].
A family of PLA2 enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA2 have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA2s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem., 264:5768-5775 (1989); and A. Kando et al, Biochem Biophys. Res. Comm., 163:4248.(1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line, designated RAW 264.7. A specific activity of 2 xcexcmols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta., 9:476492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA2.
A cytosolic phospholipase A2 (hereinafter xe2x80x9ccPLA2xe2x80x9d) has also been identified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are al desired. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states.
The present invention provides compounds having a chemical formula selected from the group consisting of: 
or a pharmaceutically acceptable salt thereof, wherein:
A is independent of any other group and is selected from the group consisting of xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94;
B is independent of any other group and is selected from the group consisting of xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2O)nxe2x80x94, xe2x80x94(CH2S)nxe2x80x94, xe2x80x94(OCH2)nxe2x80x94, xe2x80x94(SCH2)nxe2x80x94, xe2x80x94(CHxe2x95x90CH)nxe2x80x94, xe2x80x94(Cxe2x89xa1C)nxe2x80x94, xe2x80x94CON(R6)xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R6)xe2x80x94;
R1 is independent of any other R group and is selected from the group consisting of xe2x80x94Xxe2x80x94R6, xe2x80x94H, xe2x80x94OH, halogen, xe2x80x94CN, xe2x80x94NO2, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R2 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94Zxe2x80x94R5, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94R5, xe2x80x94Zxe2x80x94R5, C1-C10 alkyl, alkenyl and substituted aryl;
R3 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94Zxe2x80x94R5, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94R5, xe2x80x94Zxe2x80x94R5, C1-C10 alkyl, alkenyl and substituted aryl;
R4 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94OR6, xe2x80x94SR6, xe2x80x94CN, xe2x80x94COR6, xe2x80x94NHR6, xe2x80x94COOH, xe2x80x94CONR6R7, xe2x80x94NO2, xe2x80x94CONHSO2R8, C1-C5 alkyl, alkenyl and substituted aryl;
R5 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94O(CH2)nR6, xe2x80x94SR6, xe2x80x94CN, xe2x80x94COR6, xe2x80x94NHR6, xe2x80x94COOH, xe2x80x94NO2, xe2x80x94COOH, xe2x80x94CONR6R7, xe2x80x94CONHSO2R8, C1-C5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, xe2x80x94CF3, xe2x80x94CF2CF3 and 
R6 is independent of any other R group and is selected from the group consisting of xe2x80x94H, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R7 is independent of any other R group and is selected from the group consisting of xe2x80x94H, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R8 is independent of any other R group and is selected from the group consisting of C1-C3 alkyl, aryl and substituted aryl;
R9 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, a halogen, xe2x80x94CN, xe2x80x94OR6, xe2x80x94COOH, xe2x80x94CONR6R7, tetrazole, xe2x80x94CONHSO2R8, xe2x80x94COR6, xe2x80x94(CH2)nCH(OH)R6 and xe2x80x94(CH2)nCHR6R5;
R10 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, a halogen, xe2x80x94CN, xe2x80x94OR6, xe2x80x94COOH, xe2x80x94CONR6R7, tetrazole, xe2x80x94CONHSO2R8, xe2x80x94COR6, xe2x80x94(CH2)nCH(OH)R6 and xe2x80x94(CH2)nCHR6R5;
W is, independently each time used including within the same compound, selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94 and xe2x80x94N(P6)xe2x80x94;
X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R6)xe2x80x94;
Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CON(R6)xe2x80x94 and xe2x80x94N(R6)COxe2x80x94;
m is, independently each time used including within the same compound, an integer from 0 to 4; and
n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4.
Preferably, the compounds of the invention have phospholipase enzyme inhibiting activity. Other preferrred embodiments include compounds having the following chemical formula: 
compounds having the following chemical formula: 
compounds having the following chemical formula: 
In particularly preferred embodiments, A is xe2x80x94CH2xe2x80x94 and R2 is xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94ZR5. These preferred compounds includes those wherein n is 1, m is 1, W is xe2x80x94Sxe2x80x94 and Z is xe2x80x94COxe2x80x94; those wherein R5 is xe2x80x94NHR6; those wherein R6 is a substituted aryl group and those wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, xe2x80x94CF3, xe2x80x94CF2CF3, xe2x80x94(CH2)pCOOH, xe2x80x94(CH2)pCH3, xe2x80x94O(CH2)pCH3, xe2x80x94(CH2)pOH, xe2x80x94(CH2)pS(C6H6), xe2x80x94(CH2)pCONH2 and xe2x80x94CHR11COOH, wherein R11 is selected froup the group consisting of alkyl, alkenyl, alkynyl, xe2x80x94(CH2)pOH, and -O(CH2)pCH3, and wherein p is an integer from 0 to 4. Other preferred comounds include those wherein R1is selected from the group consisting of xe2x80x94H and xe2x80x94OCH2(C6H6) and R3 is xe2x80x94COR5, R5 is xe2x80x94OCH2R6 and R6 is a substituted aryl group. In particularly preferred compounds, said aryl group is substituted with one or more substituents selected from the group consisting of xe2x80x94CF3, xe2x80x94CF2CF3 and xe2x80x94C(CH3)2CH2CH3.
Among the compounds of this invention are those of the formula: 
wherein:
R1 and R1xe2x80x2 are independently selected from C1-C6 alkyl, xe2x80x94Zxe2x80x94C1-C6 alkyl, phenyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-phenyl, benzyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-benzyl, napthyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-napthyl, pyrimidinyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
Z is O or S;
n is an integer from 0 to 3;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl,
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94CHO, xe2x80x94C(O)CH3, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94CF3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl or a moiety of the formula: 
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R4 is selected from xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, tetrazole, xe2x80x94(CH2)n-tetrazole, the moiety xe2x80x94L1xe2x80x94M1 or a moiety of the formulae: 
R12 is selected from H, xe2x80x94CF3, C1-C6 alkyl, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
L1 is selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M1 is xe2x80x94COOH or a moiety selected from: 
R10 is selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl xe2x80x94Oxe2x80x94C1-C6 alkyl, 
with a proviso that the moiety or combination of moieties comprising R3 include an acidic group selected from carboxylic acid or a moiety of the formulae: 
R5 is selected from:
a) a moiety of the formula xe2x80x94L2xe2x80x94M2;
L2 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)nxe2x80x94Zxe2x80x94, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M2 is selected from xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
wherein R8 and R9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or
b) a moiety of the formulae: 
wherein L3 is a chemical bond or a group selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94Zxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)nxe2x80x94;
M3 is selected from xe2x80x94(CH2)nxe2x80x94C3-C5 cycloalkyl, furanyl, thienyl, pyrrolyl, 
or a pharmaceutically acceptable salt thereof.
Of the compounds in the group just defined, a preferred subset include those in which the core molecule is an indole. Within the indole group is another subset wherein R1 and R2 are hydrogen, and the moieties R3, R4, R5, R8, R9 and R10, n, L1, L2, M1 and M2 are as defined above. Within this subset is another preferred group wherein R1 is in the indole 5-position.
Also among the compounds of this invention are those of the formula: 
wherein:
R1 is selected from xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94O-phenyl, xe2x80x94S-phenyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl, or a moiety of the formula: 
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R4 is the moiety xe2x80x94L1xe2x80x94M1 or 
L1 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M1 is the moiety: 
R10 is selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
with a proviso that the combination of moieties comprising R4 include a carboxylic acid or a moiety of the formulae: 
R5 is a structure of the formula xe2x80x94L2xe2x80x94M2;
L2 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M2 is selected from xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
wherein R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt thereof.
Also preferred are compounds of the group above with the structure: 
wherein
R1 is selected from xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94O-phenyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C10 alkyl, C1-C10 alkoxy, preferably C1-C10 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl or a moiety of the formula: 
wherein R4, R5, R8, R9 and R10 are as defined above, or a pharmaceutically acceptable salt thereof.
Also among the compounds of the present invention are those of the formulae:
Among the compounds of this invention are those of the formula: 
wherein
R1 and R1xe2x80x2 are independently selected from C1-C6 alkyl, xe2x80x94Zxe2x80x94C1-C6 alkyl, phenyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)nxe2x80x94phenyl, benzyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-benzyl, napthyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-napthyl, pyrimidinyl, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
Z is O or S;
n is an integer from 0 to 3;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, -C1-C10 alkyl, C1-C10 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, C1-C10 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl or:
n in each appearance is independently selected as an integer selected from 0-3;
R4 is selected from xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CHxe2x95x90CHxe2x80x94COOH, tetrazole, xe2x80x94(CH2)n-tetrazole, the moiety xe2x80x94L1xe2x80x94M1 or a moiety of the formulae: 
R12is selected from H, xe2x80x94CF3, C1-C6 alkyl, xe2x80x94(CH2)nxe2x80x94C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
L1 is selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94;
M1 is xe2x80x94COOH or a moiety selected from: 
R8 and R9 are independently selected in each appearance from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R10 is selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
with a proviso that the moiety or combination of moieties comprising R3 include an acidic group selected from carboxylic acid or a moiety of the formulae: 
R5 is selected from:
a) a moiety of the formula xe2x80x94L2xe2x80x94M2;
L2 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)Nxe2x80x94Zxe2x80x94, xe2x80x94(CH2)nxe2x80x94Zxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M2 is selected from xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
or
or a pharmaceutically acceptable salt thereof Of the compounds in the group just defined, a preferred subset include those in which the core molecule is an indole. Within the indole group is another subset wherein R1xe2x80x2 and R2 are hydrogen, and the moieties R3, R4, R5, R8, R9 and R10, n, L1, L2, M1 and M2 are as defined above. Within this subset is another preferred group wherein R1 is in the indole 5-position.
Also among the compounds of this invention are those of the formula: 
wherein:
R1 is selected from xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94-phenyl, xe2x80x94S-phenyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R2 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94C1-C10 alkyl, preferably xe2x80x94C1-C6 alkyl, C1-C10 alkoxy, preferably C1-C6 alkoxy, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, or xe2x80x94SO2xe2x80x94C1-C6 alkyl;
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl or:
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94NH(C1-C6 alkyl), or xe2x80x94N(C1-C6 alkyl)2;
R4 is the moiety xe2x80x94L1xe2x80x94M1 or 
L1 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94SO2xe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94;
M1 is the moiety: 
R10 is selected from H, xe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94COOH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94CF3, xe2x80x94OH, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94COOH, xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
with a proviso that the combination of moieties comprising R4 include a carboxylic acid or a moiety of the formulae: 
R5 is a structure of the formula xe2x80x94L2xe2x80x94M2;
L2 is selected from a chemical bond or a bridging group selected from xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94Nxe2x80x94, or xe2x80x94(CH2)nxe2x80x94Sxe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94Nxe2x80x94;
M2 is selected from xe2x80x94C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, 
wherein R8, R9 and R10 are as defined above;
or a pharmaceutically acceptable salt thereof.
Also preferred are compounds of the group above with the structure: 
wherein
R1 is selected from xe2x80x94Oxe2x80x94C1-C6 alkyl, xe2x80x94Sxe2x80x94C1-C6 alkyl, xe2x80x94O-phenyl, xe2x80x94O-benzyl, xe2x80x94S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94OH;
R3 is selected from H, halogen, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CHO, xe2x80x94CN, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHxe2x80x94C1-C6 alkyl, xe2x80x94N(C1-C6 alkyl)2, xe2x80x94Nxe2x80x94SO2xe2x80x94C1-C6 alkyl, xe2x80x94SO2xe2x80x94C1-C6 alkyl or:
wherein R4, R5, R8, R9 and R10 are as defined above, or a pharmaceutically acceptable salt thereof.
The compounds of this invention inhibit Cytosolic Phospholipase A2 (cPLA2) activity which is required for supplying arachidonic acid substrate to cyclooxygenase-1 or 2 and 5-lipoxygenase, which in turn initiates the production of prostaglandins and leukotrienes, respectively. In addition, cPLA2 activity is essential for producing the lyso-phospholipid precursor to Platelet Activating Factor (PAF). Thus, these compounds are useful in the treatment and prevention of disease states in which leukotrienes, prostaglandins or PAF are involved. Moreover, in diseases where more than one of these agents plays a role, a cPLA2 inhibitor is more efficacious than leukotriene, prostaglandin or PAF receptor antagonists and also more effective than cyclooxygenase or 5-lipoxygenase inhibitors.
Therefore, the compounds, pharmaceutical compositions and regimens of the present invention are useful in treating and preventing the disorders treated by cyclooxygenase-2, cycloxygenase-1, and 5-lipoxygenase inhibitors or antagonists of the receptors for PAF, leukotrienes or prostaglandins. Diseases treatable by compounds, formulations and regimens of this invention include, but are not limited to, pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases; allergies and allergic reactions such as allergic rhinitis, hay fever, contact dermatitis, allergic conjunctivitis, idiopathic infiltrative disorder of the lung, alveolitis, and the like; inflammation such as that associated with arthritis or inflammatory bowel diseases; skin disorders such as psoriasis, atopic eczema, acne, ultraviolet (UV) damage, burns primary and secondary immunodeficiency dermatosis, and dermatitis; cardiovascular disorders such as atherosclerosis, angina, myocardial ischaemia, hypertension, platelet aggregation, thrombosis, allergic angioedema and the like; and renal insufficiency induced by immunological or chemical.
The drugs may also be cytoprotective, preventing damage to the gastrointestinal mucosa by noxious agents. The compounds are also useful in the treatment of adult respiratory distress syndrome, endotoxin shock and ischeamia induced injury including myocardial or brain injury.
These compounds are especially useful in the treatment of arthritic disorders, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. The compounds of this invention are further useful in the treatment of post-operative inflammation, including that following ophthalmic surgery such as cataract surgery or refractive surgery.
The compounds of this invention can be used as an antipyretic agent and in combination with other antipyretic agents known in the art.
The compounds of this invention may be utilized in methods of treating pain, particularly the pain associated with inflammation. Specific methods include, but are not limited to, those for treating centrally mediated pain, peripherally mediated pain, musculo-skeletal pain, lumbosacral pain, structural or soft tissue injury related pain, progressive disease related pain, such as oncology and degenerative disorders, neuropathic pain, which can include both acute pain, such as acute injury or trauma, pre- and post-surgical, migraine pain, dental pain, etc., chronic pains, such as neuropathic pain conditions of diabetic peripheral neuropathy, post-herpetic neuralgia and fibromyalgia, and inflammatory conditions such as osteoarthritis or rheumatoid arthritis, sequela to acute injury or trauma and cancer-related pain.
Compositions and compounds of this invention are also useful in the treatment of menstrual cramps, preterm labor, tendonitis, bursitis, allergic neuritis, cytomegalovirus infection, apoptosis, including HIV-induced apoptosis, lumbago, liver disease including hepatitis.
The methods and compositions herein are also useful in treating gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of treatment of cancer such as colorectal cancer. The compounds and compositions of the present invention are also useful for the prevention or treatment of benign and malignant tumors/neoplasia including cancers such as colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, including lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and skin cancers, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body. Neoplasias for which compositions of the invention are particularly useful are gastrointestinal cancer, Barrett""s esophagus, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, prostatic cancer, cervical cancer, lung cancer, breast cancer, and skin cancer, such as squamous cell and basal cell cancers. The compounds and methods of this invention can also be used to treat the fibrosis occuring with radiation therapy. Such compositions can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, such compositions can be used to prevent polyps from forming in patients at risk of FAP. Compounds of this invention will be useful in the treatment of cancers based on anti-angiogenic effects.
Further uses of this invention include treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury including brain edema, myocardial ischemia, and the like. Also included are treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Treatments herein of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis, and in bone resorption such as that accompanying osteoporosis. These compounds and compositions are useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer""s disease, neurodegeneration, and central nervous system damage resulting from stroke, ischemia and trauma. The compounds of this invention may also be useful in the treatment of Parkinson""s disease.
It will be understood that methods of treating or preventing the maladies listed herein comprise administering to a mammal subject to or experiencing the malady, which may also be referred to as a mammal in need thereof, a pharmaceutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt thereof.
Methods of treating pain comprise administering to a mammal subject to such pain a pharmaceutically effective amount of a compound of this invention alone or in combination with one or more additional pharmaceutically effective agents for the treatment of pain or inflammation or the related underlying medical condition. Examples of drug agents which may be combined with the present compounds are analgesics, anti-angiogenic agents, anti-neoplastic agents, These compounds may also be combined with anti-epileptic compounds that have pain alleviating properties, such as gabapentin and pregabalin.
One such combination method of this invention comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of this invention and a pharmaceutically effective amount of a nontoxic N-methyl-D-aspartate (NMDA) receptor antagonist and/or an agent that blocks at least one major intracellular consequence of NMDA receptor activation. Examples of NMDA receptor antagonists useful in these methods include dextromethorphan, dextrorphan, amantadine and memantine, or the pharmaceutically acceptable salts thereof.
Another method herein of treating inflammation and inflammatory disorders comprises the co-administration to a mammal in need thereof of an inhibitor of induced nitric oxide synthase with a compound of this invention. Administration of this combination is useful for prophylactic or therapeutic administration in a mammal experiencing or subject to an abnormally low level of nitric oxide synbthase (NOS) activity, particularly those subject to hypertension or an elevated risk of pulmonary hypertension, ischemic stroke, myocardial infarction, heart failure, progressive renal disease, thrombosis, reperfusion injury, or a nervous system degenerative disorder, such as Alzheimer""s disease, or those chronically exposed to hypoxic conditions.
The methods of this invention also include those for treating or preventing a neoplasia disorder in a mammal, including a human, in need of such treatment or prevention. The method comprises treating the mammal with a therapeutically effective amount of a compound of this invention in combination with an MMP inhibitor. These two components may further be optionally combined with one or more agents selected from an antiangiogenesis agent, an antineoplastic agent, an adjunctive agent, an immunotherapeutic agent, an analgesic agent; and/or a radiotherapeutic agent. One such multiple component therapy comprises administering to the mammal in need thereof a compound of this invention, a matrix metalloproteinase inhibitor and an antineoplastic agent.
The methods and combinations of this invention may be used for the treatment or prevention of neoplasia disorders including acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing""s sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial. squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic polypeptide, papillary serous adenocarcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm""s tumor.
Antineoplastic agents useful in the combination therapies herein include anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, Cell Pathways CP-461, docetaxel, doxorubicin, etoposide, fluorouracil, fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole, megestrol, mitoxantrone, paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa, topotecan, toremifene, vinorelbine, vinblastine, vincristine, selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone, exemestane and eflornithine (DFMO), 1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol (TSE-424) and 2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol (ERA-923).
This invention also includes methods of utilizing the compounds herein in combination with a proteinaceous interleukin-1or TNF inhibitor, such as an IL-1 receptor antagonist (IL-1ra), for preventing or treating inflammatory diseases in a mammal. Acute and chronic interleukin-1 (IL-1)-mediated inflammatory diseases of interest in these methods include, but is not limited to acute pancreatitis; ALS; Alzheimer""s disease; cachexia/anorexia; asthma; atherosclerosis; chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes); glomerulonephritis; graft versus host rejection; hemohorragic shock; hyperalgesia, inflammatory bowel disease; inflammatory conditions of a joint, including osteoarthrit is, psoriatic arthritis and rheumatoid arthritis; ischemic injury, including cerebral ischemia (e.g., brain injury as a result of trauma, epilepsy, hemorrhage or stroke, each of which may lead to neurodegeneration); lung diseases (e.g., ARDS); multiple myeloma; multiple sclerosis; myelogenous (e.g., AML and CML) and other leukemias; myopathies (e.g., muscle protein metabolism, esp. in sepsis); osteoporosis; Parkinson""s disease; pain; pre-term labor; psoriasis; reperfusion injury; septic shock; side effects from radiation therapy, temporal mandibular joint disease, tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma, orthopedic surgery, infection or other disease processes.
This invention also provides a method of administering one or more of the compounds of this invention to a female in need thereof to substantially prevent or reducing changes in the female""s reproductive system associated with onset or continuation of labor. Also provided is a method of substantially preventing or reducing uterine contractility either occurring during pregnancy or associated with menorrhagia. These methods may optionally include coadministration of a compound of this invention with a progestogen, a progestin or a progestational agent.
A pharmaceutically effective amount of a compound herein will be understood to be an amount which will inhibit, prevent or alleviate the physiological origin or symptoms of the malady or condition in question. The amount will be determined by a medical professional based upon the malady or condition in question and the personal characteristics of the recipient including, but not limited to, the recipient""s age, sex, weight, and medical history.
The present invention also provides for a method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention. Methods of treating an inflammatory response or condition, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention are also provided. Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided.
Pharmaceutically acceptable salts of the compounds of the compounds described herein are also part of the present invention and may be used in practicing the compounds and methods disclosed herein.